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CELL BIOLOGY Gene Related to Tumor Suppressor Linked to Stem Cell Pool In many of our tissues—like the skin—death is an essential part of life. Through rounds of regeneration, cells die off and are replenished from a pool of stem cells. In the April 22 Nature, researchers show that mice lacking the p63 gene are born without skin and have major defects in all tissues derived from epithelial stem cells— the skin, the mammary, salivary, and prostate glands, and others.    The study, funded in part by the NIH, brings new insight into the mechanisms that keep epithelial stem cells in a state of constant replication, essential for regenerating body tissues. The p63 gene—a close relative of the major human tumor suppressor p53—may also help scientists understand why some cells switch from controlled division to the endless proliferation that characterizes cancer.     "To our knowledge, this is the first genethat plays a role in maintenance of epithelial stem cell identity in mammals," says Frank McKeon, cell biology professor at HMS and senior author of the study. Among his collaborators are Harvard colleagues Annie Yang, first author; Cliff Tabin, professor of genetics; Ronen Schweitzer, research fellow in genetics; and Arlene Sharpe, associate professor of pathology at Brigham and Women's Hospital. Cell Origins Stem cells have gained international attention because of their ability to produce different cell types. While they harness the potential to one day allow scientists to produce most of our tissues in the lab, little is known about how they work, why they are able to constantly proliferate without crossing the line towards cancer, or which molecular instructions make them produce a cell of a specific type.    According to McKeon, p63 might be the first step to answering many of these questions, because it seems to play a role in maintaining the population of epithelial stem cells. All stem cells, he says, undergo an asymmetric division, producing a cell that will become specialized but also leaving behind a new stem cell. This process ensures that a population of stem cells will be present to replenish those specialized cells that die during the normal regenerative process.     Previous studies had shown that the protein p63 was present in high amounts in the stem cells of a wide range of human and mouse epithelial tissues like the skin, prostate, breast, and cervix. Still, when the researchers decided to make a mouse knockout of p63, it was not clear whether they would see any serious developmental defects—after all, mice lacking p53 are born normal. Figure A Figure B Figure C A) The skin of p63-deficient mice "peels off." These panels show skin of mouse embryos, at a stage when p63-knockout mice start to lose their differentiated, epidermal cells. Notice how the skin of mutant mice looks like it is exfoliating when compared to normal mice. The bottom panels of figure A show a cross-section of the skin of normal and p63-deficient embryos. Very few epithelial skin cells are left in the p63-deficient skin, while normal skin is thick and stratified. B) p63 is expressed in epithelial stem cells at the basal layer of a number of tissues, including the cervix, prostate, and urogenital epithelium. C) Based on their results, Yang and McKeon propose that p63 is essential for maintaining the population of epithelial stem cells that gives rise to tissues like the skin. Without p63, there is no epithelial stem cell population to produce new cells that can replace those that die during the normal process of tissue regeneration.     It soon became evident, however, that mice without p63 had serious problems. They were born with facial abnormalities, truncated limbs, and a complete absence of skin, as well as related structures including hair follicles and teeth.     "The challenge was then to figure out what happened to all these absent tissues," McKeon says.     The scientists investigated the limb defects and found an explanation for the truncations. In the absence of p63, a specialized ectodermal structure called the apical ectodermal ridge does not form at the tip of the growing limbs. The ridge provides essential signals for growth to the limb, so mice lacking p63 grow truncated, short limbs.     Then, when it came to understanding the defects in other tissues, looking at the mutant mice before they were born gave the McKeon group an important hint. They saw that early on, the embryos did have what appeared to be skin—only it was falling apart in clumps. The embryos were practically exfoliating, and the researchers could see layers of skin cells starting to peel off the surface of the mice.     "So we thought that if there was skin there, perhaps these mice were able to make the specialized tissues from the epithelial stem cells, and maybe their problem was that they could not maintain those tissues," McKeon says. The hunch was confirmed when the scientists looked at sections of the skin in these embryos and identified specialized epidermal cells.     "That's where it came down to realizing that p63 is really not required for the differentiation of these tissues. It is required to keep stem cells as stem cells," McKeon says. So initially, the epithelial stem cells do go on to make specialized types, but once those die as part of the natural process of tissue regeneration, there is no pool of stem cells left to replenish the supply.     Yang adds that in understanding the role of p63, an important contribution came from Christopher Crum, a professor of pathology at Brigham and Women's Hospital and a co-author on the study. "He had been looking at different events in cervical tissue, and realized that p63 was an indicator of stem cell properties. Crum therefore made a link between the presence of p63 in cells and their state of immaturity," Yang says.    That helped the authors develop their hypothesis that the defect in the mice was in the maintenance of stem cells, as opposed to the initial creation of differentiated tissue. In fact, this is the conclusion reached by a companion article published in the same Nature issue, in which a Texas group analyzed the effects of their p63-deficient mice.     "Our goal now is to find the genes controlled by p63," McKeon says. "We've got to find out what genes p63 is turning on or off to maintain the stem cell state."     He says the research on p63 may eventually have implications for cancer biology. "You have to realize that p63 seems to be involved in epithelial stem cells for tissues which probably relate to 80 percent of human cancers, and yet we know almost nothing about how the stem cell state is maintained." —Sylvia Pagán Westphal Back to Top